Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3 mutant cancer
作者： Maria Teresa Herrera-Abreu , Alex Pearson , James Campbell , Steve D Shnyder , Margaret A Knowles
DOI: 10.1158/2159-8290.CD-12-0569
关键词: Signal transduction 、 Erdafitinib 、 RNA interference 、 Fibroblast growth factor receptor 、 Cell biology 、 Genetic screen 、 Biology 、 Downregulation and upregulation 、 FGFR Inhibition 、 EGFR inhibitors
摘要: Activation of fibroblast growth factor receptors is a common oncogenic event. Little known about the determinants sensitivity to FGFR inhibition and how these may vary between different FGFRs. Using parallel RNA interference genetic screens we demonstrate that EGFR limits in FGFR3 mutant translocated cell lines, but not other driven lines. We also identify two distinct mechanisms through which sensitivity. In partially dependent results transient down-regulation MAPK signalling rescued by rapid upregulation signalling. lines are intrinsically resistant inhibition, dominates via repression FGFR3, with delayed up-regulation expression. Importantly, combinations inhibitors overcome resistance vitro vivo. Our illustrate power identifying targeted therapies.
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